Project 3: The Role of BCL-6 in Germinal Center Formation. The overall goal of this project is to elucidate the biological function of the BCL-6 proto-oncogene and its role in the pathogenesis of non-Hodgkin lymphoma (NHL). BCL-6 is a POZ-zinc finger transcriptional represser required for germinal center (GC) formation, whose expression id frequently deregulated by chromosomal translocation and somatic hypermutation in diffuse large B cell lymphoma (DLBCL). The following specific aims will be pursued: 1. A genome -wide identification of BCL6 target genes in GC B cells by integrating gene expression profiling with biochemical and reverse engineering methods;2. Construction of mouse models of DLBCL by combining BCL6 deregulation with other lesions associated human DLBCL, including IRF4/MUM1 and c-MYC deregulation, and Blimpl inactivation;3. Development and pre-clinical testing of anti-BCL6 therapeutic strategies. "Stabilized Alpha-Helices of Transcription" (SAHT) molecules directed against BCL6 will be developed in collaboration with Project 5. Anti-BCL6 SAHTs will be tested for their efficacy and specificity against GC-derived lymphomas in DLBCL cell lines and DLBCL mouse models. The proposed studies are relevant for public health since non-Hodgkin lymphomas represent the 5th most common human malignancy and are displaying an increased incidence during the last decade. This project plans to improve the understanding of the pathogenesis of this disease and develop new therapeutic strategies